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European Journal of Human Genetics: EJHG

Takahiro Otani, Hisashi Noma, Jo Nishino, Shigeyuki Matsui
Although enormous costs have been dedicated to discovering relevant disease-related genetic variants, especially in genome-wide association studies (GWASs), only a small fraction of estimated heritability can be explained by these results. This is the so-called missing heritability problem. The conventional use of overly conservative multiple testing strategies based on controlling the familywise error rate (FWER), in particular with a genome-wide significance threshold of P <5 × 10-8 , is one of the most important issues from a statistical perspective...
March 9, 2018: European Journal of Human Genetics: EJHG
Marc Woodbury-Smith
No abstract text is available yet for this article.
March 6, 2018: European Journal of Human Genetics: EJHG
Jesus Mates, Irene Mademont-Soler, Bernat Del Olmo, Carles Ferrer-Costa, Monica Coll, Alexandra Pérez-Serra, Ferran Picó, Catarina Allegue, Anna Fernandez-Falgueras, Patricia Álvarez, Raquel Yotti, Maria Angeles Espinosa, Georgia Sarquella-Brugada, Sergi Cesar, Ester Carro, Josep Brugada, Elena Arbelo, Pablo Garcia-Pavia, Mar Borregan, Eduardo Tizzano, Amador López-Granados, Francisco Mazuelos, Aranzazu Díaz de Bustamante, Maria Teresa Darnaude, José Ignacio González-Hevia, Felícitas Díaz-Flores, Francisco Trujillo, Anna Iglesias, Francisco Fernandez-Aviles, Oscar Campuzano, Ramon Brugada
Several studies have identified copy number variants (CNVs) as responsible for cardiac diseases associated with sudden cardiac death (SCD), but very few exhaustive analyses in large cohorts of patients have been performed, and they have been generally focused on a specific SCD-related disease. The aim of the present study was to screen for CNVs the most prevalent genes associated with SCD in a large cohort of patients who suffered sudden unexplained death or had an inherited cardiac disease (cardiomyopathy or channelopathy)...
March 6, 2018: European Journal of Human Genetics: EJHG
K J Low, K Stals, R Caswell, M Wakeling, J Clayton-Smith, A Donaldson, N Foulds, A Norman, M Splitt, K Urankar, K Vijayakumar, A Majumdar, Ddd Study, S Ellard, S F Smithson
CHN is genetically heterogeneous and its genetic basis is difficult to determine on features alone. CNTNAP1 encodes CASPR, integral in the paranodal junction high molecular mass complex. Nineteen individuals with biallelic variants have been described in association with severe congenital hypomyelinating neuropathy, respiratory compromise, profound intellectual disability and death within the first year. We report 7 additional patients ascertained through exome sequencing. We identified 9 novel CNTNAP1 variants in 6 families: three missense variants, four nonsense variants, one frameshift variant and one splice site variant...
March 6, 2018: European Journal of Human Genetics: EJHG
Yan Ge, Patrick Concannon
Genome-wide association and fine-mapping studies have identified over 40 susceptibility regions for type 1 diabetes (T1D), a common autoimmune disease; however, most of the disease-associated variants are noncoding, and it remains a challenge to understand their biological contributions to T1D pathogenesis. One identified T1D risk locus is located at chromosome 21q22.3 where the most likely candidate gene is UBASH3A, a negative regulator of NF-κB signaling. Various noncoding variants in UBASH3A have been shown to be associated with T1D or other autoimmune diseases...
February 28, 2018: European Journal of Human Genetics: EJHG
Anne Legrand, Karelle Benistan, Jean Michael Mazzella, Salma Adham, Michael Frank, Xavier Jeunemaitre, Juliette Albuisson
No abstract text is available yet for this article.
February 27, 2018: European Journal of Human Genetics: EJHG
Hanns Lochmüller, Dorota M Badowska, Rachel Thompson, Nine V Knoers, Annemieke Aartsma-Rus, Ivo Gut, Libby Wood, Tina Harmuth, Andre Durudas, Holm Graessner, Franz Schaefer, Olaf Riess
Although individually uncommon, rare diseases (RDs) collectively affect 6-8% of the population. The unmet need of the rare disease community was recognized by the European Commission which in 2012 funded three flagship projects, RD-Connect, NeurOmics, and EURenOmics, to help move the field forward with the ambition of advancing -omics research and data sharing at their core in line with the goals of IRDiRC (International Rare Disease Research Consortium). NeurOmics and EURenOmics generate -omics data and improve diagnosis and therapy in rare renal and neurological diseases, with RD-Connect developing an infrastructure to facilitate the sharing, systematic integration and analysis of these data...
February 27, 2018: European Journal of Human Genetics: EJHG
Diane d'Audiffret Van Haecke, Sandrine de Montgolfier
Health professionals have a role to play in assisting patients to communicate genetic information to their relatives. In France, a specific unique legal framework has been implemented concerning this issue. We questioned professionals about their practice and how it has evolved in this new frame. The French law has opted to lay responsibility for disclosure on the person concerned by a positive test result, without totally excluding some responsibility on the part of the professionals involved, in the information to be disclosed and in the transmission of the information if a patient refuses to do it themselves (indirect disclosure)...
February 27, 2018: European Journal of Human Genetics: EJHG
Wibhu Kutanan, Jatupol Kampuansai, Andrea Brunelli, Silvia Ghirotto, Pittayawat Pittayaporn, Sukhum Ruangchai, Roland Schröder, Enrico Macholdt, Metawee Srikummool, Daoroong Kangwanpong, Alexander Hübner, Leonardo Arias, Mark Stoneking
Tai-Kadai (TK) is one of the major language families in Mainland Southeast Asia (MSEA), with a concentration in the area of Thailand and Laos. Our previous study of 1234 mtDNA genome sequences supported a demic diffusion scenario in the spread of TK languages from southern China to Laos as well as northern and northeastern Thailand. Here we add an additional 560 mtDNA genomes from 22 groups, with a focus on the TK-speaking central Thai people and the Sino-Tibetan speaking Karen. We find extensive diversity, including 62 haplogroups not reported previously from this region...
February 26, 2018: European Journal of Human Genetics: EJHG
Anna Norberg, Anna Rosén, Klas Raaschou-Jensen, Lars Kjeldsen, Jukka S Moilanen, Ylva Paulsson-Karlsson, Panagiotis Baliakas, Olli Lohi, Aymen Ahmed, Astrid O Kittang, Pär Larsson, Göran Roos, Sofie Degerman, Magnus Hultdin
Telomere-related disorders are a clinically and genetically heterogeneous group of disorders characterized by premature telomere shortening and proliferative failure of a variety of tissues. This study reports the spectrum of telomere-related gene variants and telomere length in Nordic patients referred for genetic testing due to suspected telomere-related disorder. We performed Sanger sequencing of the genes TERT, TERC, DKC1, and TINF2 on 135 unrelated index patients and measured telomere length by qPCR on DNA from peripheral blood leukocytes...
February 26, 2018: European Journal of Human Genetics: EJHG
Emil V R Appel, Ida Moltke, Marit E Jørgensen, Peter Bjerregaard, Allan Linneberg, Oluf Pedersen, Anders Albrechtsen, Torben Hansen, Niels Grarup
We previously showed that a common genetic variant leads to a remarkably increased risk of type 2 diabetes (T2D) in the small and historically isolated Greenlandic population. Motivated by this, we aimed at discovering novel genetic determinants for glycated hemoglobin (HbA1C ) and at estimating the effect of known HbA1C -associated loci in the Greenlandic population. We analyzed genotype data from 4049 Greenlanders generated using the Illumina Cardio-Metabochip. We performed the discovery association analysis by an additive linear mixed model...
February 26, 2018: European Journal of Human Genetics: EJHG
Matthieu Egloff, Lam-Son Nguyen, Karine Siquier-Pernet, Valérie Cormier-Daire, Geneviève Baujat, Tania Attié-Bitach, Christine Bole-Feysot, Patrick Nitschke, Michel Vekemans, Laurence Colleaux, Valérie Malan
Several hypotheses have been proposed to explain the phenotypic variability between parent and offspring carrying the same genomic imbalance, including unmasking of a recessive variant by a chromosomal deletion. Here, 19 patients with neurodevelopmental disorders harboring a rare deletion inherited from a healthy parent were investigated by whole-exome sequencing to search for SNV on the contralateral segment. This strategy allowed us to identify a candidate variant in two patients in the NUP214 and NCOR1 genes...
February 26, 2018: European Journal of Human Genetics: EJHG
Niklas Darin, Karin Leckström, Per Sikora, Julia Lindgren, Gabriella Almén, Jorge Asin-Cayuela
γ-Glutamyl transpeptidase deficiency (glutathionuria, OMIM 231950) is a rare disease, with only six patients reported in the literature, although this condition has probably been underdiagnosed due the difficulty to routinely analyze glutathione in clinical samples and to the fact that no genetic defect has been coupled to the disease so far. We report two siblings with mild psychomotor developmental delay and mild neurological symptoms, who presented a markedly increased excretion of glutathione in urine and a very low γ-glutamyl transpeptidase activity in serum...
February 26, 2018: European Journal of Human Genetics: EJHG
Clara Sm Tang, Xuehan Zhuang, Wai-Yee Lam, Elly Sau-Wai Ngan, Jacob Shujui Hsu, Y U Michelle, S O Man-Ting, Stacey S Cherny, Ngoc Diem Ngo, Pak C Sham, Paul Kh Tam, Maria-Mercè Garcia-Barcelo
Hirschsprung disease (HSCR) is a complex birth defect characterized by the lack of ganglion cells along a variable length of the distal intestine. A large proportion of HSCR patients remain genetically unexplained. We applied whole-genome sequencing (WGS) on 9 trios where the probands are sporadically affected with the most severe form of the disorder and harbor no coding sequence variants affecting the function of known HSCR genes. We found de novo protein-altering variants in three intolerant to change genes-CCT2, VASH1, and CYP26A1-for which a plausible link with the enteric nervous system (ENS) exists...
February 26, 2018: European Journal of Human Genetics: EJHG
Natalia Teixeira, Annemieke van der Hout, Jan C Oosterwijk, Janet R Vos, Peter Devilee, Klaartje van Engelen, Hanne Meijers-Heijboer, Rob B van der Luijt, Mieke Kriege, Arjen R Mensenkamp, Matti A Rookus, Kees E van Roozendaal, Marian J E Mourits, Geertruida H de Bock
This observational study aimed to investigate whether the reported association between family history (FH) of breast cancer (BC) or ovarian cancer (OC) and OC risks in BRCA1/2 mutation carriers can be explained by mutation position on the gene. In total, 3310 female BRCA1/2 mutation carriers participating in a nationwide prospective cohort (Hereditary Breast and Ovarian Cancer in the Netherlands) were included. FH was classified according to cancer occurrence in first-degree relatives (BC only, OC only, both, neither) and mutations were classified according to their position on the gene (OC cluster region (OCCR), BC cluster region, neither)...
February 26, 2018: European Journal of Human Genetics: EJHG
Dan Zhcou, Dandan Zhang, Xiaohui Sun, Zhiqiang Li, Yaqin Ni, Zhongyan Shan, Hong Li, Chengguo Liu, Shuai Zhang, Yi Liu, Ruizhi Zheng, Feixia Pan, Yimin Zhu, Yongyong Shi, Maode Lai
Although numbers of genome-wide association studies (GWAS) have been performed for serum lipid levels, limited heritability has been explained. Studies showed that combining data from GWAS and expression quantitative trait loci (eQTLs) signals can both enhance the discovery of trait-associated SNPs and gain a better understanding of the mechanism. We performed an annotation-based, multistage genome-wide screening for serum-lipid-level-associated loci in totally 6863 Han Chinese. A serum high-density lipoprotein cholesterol (HDL-C) associated variant rs1880118 (hg19 chr7:g...
February 23, 2018: European Journal of Human Genetics: EJHG
Erin Turbitt, Megan C Roberts, Rebecca A Ferrer, Jennifer M Taber, Katie L Lewis, Leslie G Biesecker, Barbara B Biesecker, William Mp Klein
Given familial implications of genetic information, it is important to understand intentions to share carrier results with family members. To our knowledge, no studies among individuals undergoing exome sequencing have used dyadic data analysis to examine the effect of spousal perceptions and beliefs. Survey responses from 136 individuals (68 couples) undergoing exome sequencing in a research study were analyzed using dyadic analysis (the actor-partner interdependence model). Intention to share carrier results with family members was correlated between spouses (ICC = 0...
February 23, 2018: European Journal of Human Genetics: EJHG
Petra Pasanen, Liisa Myllykangas, Minna Pöyhönen, Anna Kiviharju, Maija Siitonen, John Hardy, Jose Bras, Anders Paetau, Pentti J Tienari, Rita Guerreiro, Auli Verkkoniemi-Ahola
Alzheimer's disease (AD) and frontotemporal dementia (FTD) are the two most common neurodegenerative dementias. Variants in APP, PSEN1 and PSEN2 are typically linked to early-onset AD, and several genetic risk loci are associated with late-onset AD. Inherited FTD can be caused by hexanucleotide expansions in C9orf72, or variants in GRN, MAPT or CHMP2B. Several other genes have also been linked to FTD or FTD with motor neuron disease. Here we describe a cohort of 60 Finnish families with possible inherited dementia...
February 23, 2018: European Journal of Human Genetics: EJHG
Ruiqing Fu, Siti Shuhada Mokhtar, Maude Elvira Phipps, Boon-Peng Hoh, Shuhua Xu
Copy number variations (CNVs) are genomic structural variations that result from the deletion or duplication of large genomic segments. The characterization of CNVs is largely underrepresented, particularly those of indigenous populations, such as the Orang Asli in Peninsular Malaysia. In the present study, we first characterized the genome-wide CNVs of four major native populations from Peninsular Malaysia, including the Malays and three Orang Asli populations; namely, Proto-Malay, Senoi, and Negrito (collectively called PM)...
February 23, 2018: European Journal of Human Genetics: EJHG
Carmel J W Stock, Elisabetta A Renzoni
The interplay between genetic and environmental factors is likely involved in the pathogenesis of systemic sclerosis (SSc). Interstitial lung disease associated in the context of SSc (SSc-ILD) is associated with significant morbidity, and is the leading cause of death in SSc. The spectrum of SSc-ILD severity is wide, ranging from patients with only limited and inherently stable pulmonary involvement, to those with extensive and progressive pulmonary fibrosis. In order to provide accurate prognostic information for patients, and to initiate appropriate monitoring and treatment regimens, the ability to identify patients at risk of developing severe ILD early in the disease course is crucial...
February 23, 2018: European Journal of Human Genetics: EJHG
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